Chronic exercise training, consisting of repeated bouts of exercise over a sustained period, has undisputed effects to improve whole-body glucose homeostasis and insulin sensitivity, adaptations critical for people with diabetes. While these beneficial adaptations to training are well described, the underlying cellular and molecular mechanisms are not fully understood. Although the effects of exercise training have largely been investigated in the context of adaptations to skeletal muscle, there has been little investigation into the role that other tissues may play in mediating the effects of exercise training on glucose homeostasis. Preliminary data generated for this application show that transplantation of subcutaneous white adipose tissue from exercise trained mice into sedentary recipients dramatically improves glucose tolerance, well above what occurs in adipose tissue transplanted from untrained animals. This effect is short-lived, present at 9 days post- transplantation and gone by 4 weeks. In addition, the increase in glucose tolerance is associated with an increase in skeletal muscle glucose uptake. Based on these findings, this project is designed to test the novel hypothesis that that exercise training causes adaptations to subcutaneous adipose tissue that result in secretion of adipokines that in turn function in a paracrine or endocrine manner to improve whole body and skeletal muscle glucose homeostasis. There are two specific aims: 1) To determine if subcutaneous adipose tissue from exercise trained mice has paracrine or endocrine effects to increase whole body metabolic homeostasis, increase skeletal muscle glucose uptake, and increase insulin signaling; and 2) To identify adipokines from subcutaneous adipose tissue of exercise trained mice that function to improve whole body and skeletal muscle glucose metabolism. This project should identify novel adipocyte-derived factors that function to mediate the beneficial effects of exercise training on whole body and skeletal muscle glucose homeostasis. These studies have the potential to significantly impact the treatment of obesity and type 2 diabetes. PUBLIC HEALTH RELEVANCE: Diabetes is a major public health problem and exercise has an undisputed role in the treatment and prevention of this disease. The goal of this research proposal is to discover how exercise training causes fundamental changes to adipose tissue that signal the body to improve glucose uptake in skeletal muscle and overall glucose homeostasis. This will lead to a better understanding of the beneficial effects of exercise in diabetes and could help to identify novel therapies for diabetes.